6beta, 19-oxido-16, 17-acetals and ketals of the pregnane series and intermediates therefor



United States Patent More particularly, this invention relates to the provision of steroids of the formula t C=O wherein Y is hydrogen; Z is hydrogen and together Y and Z is wherein P is hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; Q is lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; or together with the carbon to which they are joined P and Q is a monocyclic cycloalkyl or monocyclic heterocyclic radical.

The compounds of this invention are physiologically active substances which possess pr-ogestational activity when administered both in the form of tablets and as a solution or suspension and hence can be used in lieu of known progestational agents such as progesterone in the treatment of habitual abortion, for which purpose they can be administered in the same manner as progesterone, for example, the dosage being adjusted for the relative potency of the particular steroid.

The compounds of the instant invention may be prepared by the process of the invention as illustrated by the following equations wherein P and Q are as hereinbefore defined and R, R and R" may be hydrogen, alkyl or acyl; and X is halogen:

(EH CH 3,235,545 Patented Feb. 15, 196.6

(X) R=CH CO (XI) R=H (XII) Ro=o= In the first step of the process of this invention, the 16,17-acetal and ketal derivatives of BaacylQXy-A pregnene-16,17-diol (Compounds A) are treated with a haloacetamide, for example, N-bromoacetamide to yield the 5-halo-6-hydroxy derivatives thereof (Compounds B). The Compound A starting materials may be prepared according to the process set forth in co-pending application, Serial No. 264,688, filed March 12, 1963 in the name of Patrick Andrew Diassi.

The 5-halo-6-hyd-r-oxy derivatives (Compounds B) are then dehydrohalogenated as by treatment with potassium carbonate to yield the 5,6-epoxy derivatives (Compounds C) which are new compounds of this invention. When in the formulae set forth in this application and the ,appended claims, a curved line (I) is employed in the linkage of atoms, it is meant to denote that the connected atom may be either in the alpha or beta position, 138 is determined in the respective compound-s involved.

The 5,6-epoxy derivatives (Compounds C) maythen be treated with an acid, for example, perchloric acid to yield the 5,6-dioxygenated derivatives (Compounds D which are also new compounds of this invention.

Compounds D may then be oxidized as by treatment With lead tetraacetate to yieldthe 6,19-oxido derivatives of this invention (Compounds E) which are also new products of this invention.

Compounds E may then be oxidized and treated with a hydrogen halide, for example, hydrogen chloride in an acid medium, for example, acetic acid, to yield the 65,19- oxidoprogesterone derivatives (Compounds G).

The acyl radicals preferred in the practice of this invention are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric and tertpentanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g., phenacetic and fi-phenylpropionic acids), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

This invention may be further illustrated by the following examples:

EXAMPLE 1 5a-br0mo-I6a,17u-dimethylmetkylenedioxypregnanedfl- 6,8-dil-20-0ne 3-acetale To a solution of 355 grams of l6a,17ot-dimethylmethylenedioxy-A -pregnene-3,8-ol-20-one 3-acetate in 16.6 liters of dioxane bromoacetamide are added and the resulting solution kept in the dark at room temperature for two hours during which time it turns amber in color. A 5% solution of sodium sulfite is then added until the solution turns colorless. It is then diluted with 19 liters of water and extracted with chloroform. The chloroform extracts are washed with water and evaporated to dryness in vacuo. Crystallization of the residue from acetonehexane gives 172 grams of 5ot-bI0H1O-160t,17ot-d1ll16lhYimethylenedioxypregnane-313,6;3-diol-20-one 3-acetate having a melting point of about 15 8-160".

Similarly, following the procedure of Example 1, but substituting other haloacetamides for N-bromoacetamide, for example N-chloroacetamide there is obtained the respective 542-11310 derivative, for example, 5oc-chloro derivative.

EXAMPLE 2 5a, 6oz-0xid0-16a,1 7a-dimethylmethylenedioxypregnane- 3,8-ol-20-0ne S-acetate The procedure of Example 1 is followed and the mother liquors of the crystallization are evaporated to dryness and the residue dissolved in 6 liters of chloroform hexane (1:1, v.:v.). This solution is adsorbed on to 6 kilograms of Woelm neutral alumina (Activity I). Elution with chloroform, evaporation of the eluates in vacuo, and crystallization of the residue obtained therefrom gives 5a,6aoxido-16a,17u dimethylmethylenedioxypregnane 3 ,3 ol- 20-one 3-acetate having a melting point about 200- 202 C., -12 (chloroform).

Anal.Calcd for C H O (446.56): C, 69.93; H, 8.58. Found: C, 69.94; H, 8.53.

EXAMPLE 3 16:1,] 7ot-dim ethylmethylenediovypregnmze-3fi,5a,6,8- tri0l-20-one 3 -acetate Following the procedure of Example 2, and further eluting the alumina with ethyl acetate and crystallization of the residue yields 3.2 grams of l6a,l7u-dimethylmethylenedi0xypregnane-3,B,5a,6fi-rtiol-20-one 3-acetate having a melting point 283-285 C., +11 (chloroform).

Anal.-Calcd. for C H O (464.58): C. 67.21; H,

8.68. Found: C, 67.34; H, 8.77.

EXAMPLE 4 5a,60c-0xid0-l6a,1 7otdimethylmethylenedioxypregnane- 3B-0l-20-0ne EXAMPLE 5 160a,] 7a-dimeflzylmelhylened i0xypregnane-3 5,5 11,65- tl i0l-20-0ne To a solution of 200 mg. of 16a,17u-dimethylmethylenedioxypregnane-3p,5u,Gfl-triol-ZO-one 3-acetate in 8 ml. of

methanol, there is added 2.0 m1. of 1% potassium carbonate and the solution stirred at room temperature for four hours. It is then neutralized with 10% acetic acid, diluted with water and extracted with chloroform. The chloroform is separated, evaporated to dryness in vacuo and the residue crystallized from acetone-hexane to give 106 mg. of 16oz,17a-dimethylmethylenedioxypregnane-3 3, 5a,6/3-triol-20-one having a melting point of 231-233" C., [111 +34 (chloroform).

Anal.-Calcd. for C H O (422.57): C, 68.22; H, 9.07. Found: C, 68.37; H, 8.96.

EXAMPLE 6 16cc,] 7 a-dimethylmethylenedioxypregnanefifij 00,6 3- triol-ZO-one 3,6-diacetate A solution of 200 mg. of 16a,l7a-dimethylmethylenedioxypregnane 3B,5a,6B-triol-20-one S-acetate in 3 ml. of anhydrous pyridine and one ml. of acetic anhydride is kept at room temperature for fifty-four hours. The acetic anhydride is decomposed by slow addition of ice and the mixture distributed between chloroform and water. The chloroform is Washed with 2 N hydrochloric acid then with water until neutral and the chloroform evaporated to dryness in vacuo. Crystallization of the residue from acetone-hexane gives 160 mg. of 16a,17a-dimethylenedioxypregnane-3/3,5a,6B-triol-20-one 3,6-diacetate having a melting point of about 236-238 C., (chloroform).

Anal.Calcd. for C H O (506.62): C, 66.38; H, 8.36. Found: C, 66.46; H, 8.37.

EXAMPLE 7 1 601,1 7a-dimethy lm ethylenedioxypregnane-3 19,50:- dial-6,20-dione 3-acetate To a solution of mg. of 16a,17u-dimethylmethylenedi0xypregnane-35,5u,65-triol-20-one 3-acetate in 5 ml. of reagent grade acetone is added dropwise an aqueous solution containing 20 mg. of chromic anhydride and 32 mg. of sulfuric acid per ml. until it is no longer decolorized. After stirring for ten minutes the excess chromic anhydride is decomposed by methanol and the solution diluted slowly with water. The crystals which separate are filtered, washed with water, and dried to give 70 mg. of 16m,17adimethylmethylenedioxypregnane-3 B,5a-diol-6,20-dione 3- acetate having melting point 273275, [M +4.0 (chloroform) AnaL-Calcd. for C H O (466.57): C, 67.51; H, 8.28. Found: C, 67.53; H, 8.29.

EXAMPLE 8 5 9,6/3-0xid0-1 60,1 7 a-dimethylmethylenedioxypregnwne- 3fi-0l-20-0ne A solution of 450 mg. of 5a-bromo-16a,17a-dimethylmethylenedioxypregnane-35,6,8-diol-20-one 3-acetate in 25 ml. of methanol is treated with 5 ml. of 10% potassium carbonate and stirred at room temperature for twenty minutes. It is then neutralized with 10% acetic acid, diluted with water and extracted with chloroform. The chloroform is washed with water and evaporated to dryness in vacuo. Crystallization of the residue from acetone-hexane gives 250 mg. of 5fi,6fi-0XidO-160L,17rx-dimethylmethylenedioxypregnane-3 3-ol-20-one having a melting point of about 205207 C., M1 +37 (chloroform).

Anal-Calcd. for C H O (404.55): C, 71.25; H, 8.97. Found: C, 70.76; H, 9.00.

EXAMPLE 9 A solution of 100 mg. of 5,8,65-oxido-16m,17x-dirnethylmthylenedioxypregnane-3B-ol-ZO-one in 3 ml. of anhydrous pyridine and 1 ml. of acetic anhydride is left at room temperature for sixteen hours and then slowly diluted with ice water. The crystals which separate are 5 filtered, washed with water, and dried to give 99 mg. of 55,6 3 oxido 16a,17x dimethylmethylenedioxypregnane-3fl-ol-20-one 3-acetate having a melting point of 133-135 C., +26 (chloroform).

Anal.-Calcd. for C H O (446.59): C, 69.93; H, 8.58. Found: C, 69.27; H, 8.59.

EXAMPLE 10 6,8,19-xid016a,17a-dimethylmethylenedioxypregnane- 3 3,5 oc-diOl-Z O-one 3 ace tate A suspension of 8.9 g. of lead tetraacetate which has been dried under high vacuum over potassium hydroxide, and 2.9 g. of calcium carbonate which has been dried over phosphorus pentoxide, in 110 ml. of cyclohexane is stirred under reflux for ten minutes. A solution of 2.0 gram of 16a,17u-dimethylmethylenedioxypregnane-3 8, 50:,6B-t1i01-20-0116 in 315 ml. of benzene is then added followed by 2.54 g. of iodine and the mixture is stirred under reflux with irradiation from a 250 watt lamp for four hours, during which time the iodine color disappears. The reaction mixture is then filtered, washed with 300 ml. portions of methylene chloride and ethyl acetate, respectively. The combined filtrate is then washed successively with 500 ml. of 5% potassium iodide, sodium sulfite and water, dried over magnesium sulfate and evaporated to dryness, in vacuo. Crystallization of the residue gives 613,19 oxido 16a,17a dimethylmethylenedioxypregname-3,8,5u-di0l-20-one 3-acetate.

EXAMPLE 11 6B,19-0xid0-16u,1 7 u-dimethylmethylenedioxy pregnanc- 313,5 a-diol-20-one To a solution of 500 mg. of 6,8,19-0Xld0-16a,17a-dlmethylmethylenedioxypregnane 3,6,50; diol 20 one 3- acetate in 25 ml. of methanol 5 ml. of 10% potassium carbonate is added and the mixture stirred at room temperature for one hour. It is then neutralized with 10% acetic acid, diluted with water, and extracted with chloroform. The chloroform extract is washed with water and evaporated to dryness in vacuo. Crystallization of the residue gives 6fi,19-oxido-16a,17a-dimethylmethylenedioxypregnane-3 8,5a-diol-20-0ne.

EXAMPLE 12 6fi,19-0xid0-16a,1 7a-dimethylmethylenedioxypregnane- 5 oc-ol-3,20-dione To a solution of 200 mg. of 6/3,19-oxido-l6a,17a-dimethylmethylenedioxypregnane-3 8,5a-diol-20-one in ml. of reagent grade acetone an aqueous solution containing mg. of chromic anhydride and 32 mg. of sulfuric acid per ml. of solution is added dropwise until the oxidizing reagent is no longer decolorized. After ten minutes the excess oxidizing agent decomposed with methanol and the solution carefully diluted with water. The crystals which separate are filtered, washed with water, and dried to give 618,19-oxido-16a,17a-dimethylmethylenedioxypregnane-5a-ol-3,20-dione.

EXAMPLE 13 6,8,19-0xid0-16a,17u-dimethylmethylenedioxy progesterone To a solution of 15 mg. of 6;3,19-OXlClO-16ot,l7a-di methylmethyenedioxypregnane5a-01-3,ZO-dione in 5 ml. of acetic acid a slow stream of dry hydrogen chloride is passed for two minutes. After eighteen hours at room temperature, dilute sodium bicarbonate is added and the mixture extracted with ethyl acetate. The ethyl acetate is washed with water, dried over sodium sulfate and evaporated in dryness. Purification of the residue by chromatography on alumina gives 613,19-oxido-16a,l7a-dimethylmethylenedioxyprogesterone having a melting point of about 2l3214 0., 42 (chloroform).

Similarly, if the procedures of Example 1 to 15 are carried out but other 16,17-acetal and ketal derivatives are 6 employed as starting materials, the respective 16,17-acetal and ketal final products are obtained.

EXAMPLE 14 16a,] 7a-di methylmethylenedioxypregnane- 3 6,5 11,6 fi-triol-ZO-one A solution of 200 mg. of 5a,6a-oxido-16a,17u-dimethylmethylenedioxypregnane 3,8-01- 20 one 3-acetate in a mixture of 6.5 ml. of dioxane and 1.75 ml. of 2 molar perchloric acid is stirred at room temperature for 48 hours. The solution is then diluted with water and extracted with chloroform. The chloroform phase is washed with water until neutral and then evaporated to dryness, in vacuo. Crystallization of the residue from acetone-hexane gives :,1700- dimethylmethylenedioxypregnane-3/3,5u,6,B-triol-20-one.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound of the formula wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms; R is selected from the group consisting of hydrogen, the acyl radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms and together OR are oxo; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic aryl, monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group consisting of monocyclic cycloalkyl and monocyclic heterocyclic.

2. A compound of the formula wherein R is selected from the group consisting of hydrogen, the acyl radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms and together OR are oxo; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group consisting of rnonoeyclic cycloalkyl and monocyclic heterocyclic.

3. 1601,17oc dimethylmethylenedioxypregnane 3fl,5a, 6/i-trio1-20-one 3-acetate.

4. 1605,1704 dimethylrnethylenedioxypregnane 3 6,501, 6,8-trioI-20-one.

5. 160:,170: dimethylmethylenedioxypregnane 355a, 6 3-trio1-20-one 3,6-diacetate.

6. 160:,17a dimethylmethylenedioxypregnane 35,5:2, diol-6, ZO-dione 3-acetate.

7. 6,8,19 oxide-16cc,17a-dimethy1methy1enedioxypregmane-3,6,M-diol-20-one 3-acetate.

8. 65,19 oxido-16a,17a-dimethylmethylenedioxypregnane-3B,5a-diol-20-0ne.

9. 6/3,19 oxido-l6a,17a-dirnethylmethylenedioxypregnane-5a-ol-3,20-dione.

References Cited by the Examiner UNITED STATES PATENTS 3,107,240 10/1963 Ringold et a1. 260-23955 LEWIS GOTTS, Primary Examiner.

HENRY A. FRENCH, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,235,545 February 15, 1966 Patrick A. Diassi It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 15 to 25, for that portion of the formula reading OZ" read -OZ column 3, line 44, for "dimethylmethylenediovypregnane" in italics, read -dimethylmethylenedioxypregnane in italics; line 49, for -rti0l read -triolline 57, for "5 ,6 -oxide" read S 6 oxido line 59, for "25 mil." read 25 ml column 6, line 45, for "aryl," read and lines 55 to 69, the upper right-hand portion of the formula should appear as shown below instead of as in the patent Signed and sealed this 7th day of February 1967.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

2. A COMPOUND OF THE FORMULA 